1. Field of the Invention
The present invention relates to novel compounds and pharmaceutical preparations including the same which are useful in the treatment of sickle cell disease.
2. Description of the Prior Art
Sickle cell disease is caused by a hemoglobin mutant called hemoglobin S, known as HbS. The mutation of HbS involves the replacement of a polar residue, glutamic acid, by a hydrophobic one, valine, in the 6th position of the .beta.-chains, and this renders the HbS capable of polymerization in the deoxygenated form. See Pauling et al., Science 110, 543 (1949); Ingram: Nature, (London) 178, 792 (1956). In the deoxygenated state, the HbS molecules aggregate in the form of elongated microtubular structures which distort the shape of the red cell to a sickle shape. The sickled cells tend to block the blood capillaries and ultimately give rise to the sequelae of sickle cell disease.
There are known compounds which affect polymerization of HbS, and there is a clear distinction between those which are antisickling agents and those which are antigelling agents.
The antisickling agents are those which are able to pass through the cell membrane of the erythrocytes and prevent or reverse sickling; the antigelling agents are those which are adapted to prevent polymerization of deoxygenated HbS, but which do not pass through the cell membrane in sufficient quantities and thus are not adapted to prevent or reverse sickling when contacted with red blood cells of a patient suffering from sickle cell disease.
Antigelling agents are not capable of preventing sickling, nor are they adapted to reverse sickling when incubated with erythrocytes.
In this regard, Tables II and III of U.S. Pat. No. 4,390,526 disclose various antisickling and antigelling agents, respectively, which have been developed in prior efforts to alleviate the deleterious effects of sickle cell disease. Known antisickling agents disclosed therein include DL-glyceraldehyde, various aldehydes and ketones, alkyl urea and urea, 2(benzoyl amino) pyridinium benzoate, dibromo aspirin, 3,4-dihydro-2,2-dimethyl 2H-1 benzopyridinium-6-butyric acid, pyridoxal, cystamine, nitrogen mustard, potassium cyanate, dimethyl adipimidate, and benzyl esters of certain amino acids. Cited antigelling agents include triand tetrapeptides, aromatic compounds, aromatic amino acids and peptides, and oligopeptides.
Sickle cell disease has been studied extensively, but in spite of this there does not exist a universally acceptable therapeutic agent for the treatment of this disease. During recent years attempts have been made to provide such agents. Some of these efforts are based on the use of three types of compounds:
a. Agents which bind covalently with the hemoglobin molecule;
b. Agents which bind non-covalently to this molecule; and
c. Agents affecting the cell membrane.
A number of known antisickling agents have a rather high toxicity, one of these being, for example, potassium cyanate. Moreover, it is generally agreed that none of the known agents for treating sickle cell anemia provide satisfactorily efficacious results over prolonged periods of time.
It would therefore be highly desirable to provide an active agent which is effective in preventing the sickling of erythrocytes in sickle cell patients, without the accompanying toxicity that is characteristic of many prior art treating agents.